The power of rational design

Griselimycin (GM) is a cyclic peptide from one of the Streptomyces strains. The molecule has been known since the 1960s. A research program, initiated at Rhône-Poulenc in those early days, was shelved in the 1970s due to the short plasma elimination half-life of GM upon oral administration. Now Rolf Müller of the Helmholtz Institute for Pharmaceutical Research in Saarland and researchers at Sanofi-Pasteur report in Science on the derivatives of GM with excellent anti-tuberculosis potential. Surface plasmon resonance has revealed DnaN (the sliding clamp of DNA polymerase) to be the target of this molecule. What’s most interesting is the effect of proline alkylation on the stability of GM. Apparently, proline-8 was identified as the locus of metabolic liability, which triggered the search for more stable versions of GM. Simple structural modifications led to metabolically stable compounds with increased lipophilicity and oral bioavailability of up to 89%. A crystal structure of the cyclohexyl GM-DnaN complex was determined, showing that one of the peptide-binding pockets of DnaN had been occupied by the cyclic part of the ligand. I continue to marvel at how some minute structural changes lead to profound consequences in the activity of cyclic peptides. And please don’t tell me that biological methods (phage display, you name it) are better than rational design based on logical arguments. This paper is a great example of the synthetic approach.

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http://www.sciencemag.org/content/348/6239/1106.full

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